Disability in mitochondrial aerobic metabolism and Mg2+ transport: linking biomarkers and mechanisms of ischemic heart disease to diesel particulate matter exposure

Background: Ischemic heart disease (IHD) is a major cardiovascular health concern. In addition to metabolic and behavioral risks, diesel particulate matter (DPM), with a widely exposed population, is an important external environmental risk factor for IHD. However, the effect biomarkers used to diagnose DPM-caused IHD and underlying mechanisms remain unknown. We investigated the biomarkers and underlying mechanisms of DPM in relation to myocardial hypoxia injury.

Methods: This study applied a unique population of diesel engine testers with stable DPM exposure. Electrocardiogram examination, echocardiogram examination, serum levels of myocardial Enzymes, and 6-min walking test were used for the myocardial risks assessment. A mouse model exposed to occupational environmental DPM dose and in vitro models of DPM-induced myocardial hypoxia injury were used for assessment of mitochondrial aerobic metabolism via the oxygraph-2k system, western blotting, and kits. Ion fluorescence probes, ion supplements, and mitochondrial RNA splicing protein 2 (Mrs2) overexpression transfection were used in further investigations and verifications of the mechanism of mitochondrial Mg²⁺ deficiency.

Results: We identified compromised myocardial mitochondrial aerobic metabolism as a precursor biomarker for the cardiac risk of myocardial hypertrophy and hypoxia injury in DPM exposure. DPM induce mitochondrial Mg²⁺ deficiency of cardiomyocytes, which in turn disrupt the mitochondrial aerobic metabolism processes, including the tricarboxylic acid cycle, Oxidative Phosphorylation, and ATP synthesis. Mg²⁺ deficiency is mediated by the disruption of Mg²⁺ transport proteins, such as DPM-enhanced hyperubiquitination and degradation of Mrs2, a protein responsible for mitochondrial Mg²⁺ uptake.

Conclusions: Our findings show that compromised mitochondrial aerobic metabolism, associated with Mg²⁺ deficiency, serves as a critical biomarker for DPM-induced IHD and represents a promising investigative avenue for intervention.